Preliminary results of a phase I trial of ABT-888, a poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with cyclophosphamide.

Abstract

3000 Background: ABT-888 is a potent, oral inhibitor of PARP-1 and PARP-2. In preclinical studies, ABT-888 enhances the cytotoxicity of cyclophosphamide (C). We conducted a phase I study to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of ABT-888 and C, and PAR levels in peripheral blood mononuclear cells (PBMCs). Methods: Patients with advanced cancer (ECOG PS 0-2) were enrolled. Dose escalations of ABT-888 (10–50 mg) every 12 h on days 1-4 plus C (450-750 mg/m2) on day 3 every 21 days were evaluated. Blood samples were collected during cycles 1 and 2 for measurement of ABT-888, C, and PAR. Results: 18 patients received ABT-888/C (mg/m2) at doses of 10/450 (3), 20/450 (3), 50/450 (6), 50/600 (3), and 50/750 (3). Mean age 55 years (37-76); 11 females; 7 males. Tumor types were breast (5), ovarian (4), and other (9). Mean cycles were 4 (1–16). Drug-related toxicities (mostly grade 1 or 2) were fatigue (28%), neutropenia (11%), thrombocytopenia (6%), and vomiting (6%). DLT of grade 2 thrombocytopenia that caused a delay of >2 weeks in starting cycle 2 occurred in a NHL patient treated with 50/450 of ABT-888/C. No further DLTs have been observed with dose escalation of C to 600 and 750 mg/m2. PK analysis showed a dose proportional increase in ABT-888 AUC. ABT-888 reached steady-state plasma concentrations by D3. The AUC0-inf (μ g·h/mL) and clearance (L/h) of ABT-888 at 50 mg were not significantly changed on cycle1 D1 (2.71 ± 0.8) and (19.6 ± 4.5), compared to cycle 2 D1 (2.68 ± 1.2) and (21.6 ± 7.5), respectively. The AUC and clearance of C were not altered by ABT-888 (p>0.15). Eleven patients had PARP inhibited by >50% in PBMCs by day 4. One patient with prostate cancer had a partial response and >90% inhibition of PARP activity in PBMCs; 4 patients (male breast cancer, bladder, NSCLC, and colon) had stable disease > 8 weeks. Conclusions: ABT-888 50 mg every 12 h can be safely combined with 750 mg/m2 of C. ABT-888 does not alter the PK of C. PARP inhibition occurs in PBMCs with ABT-888 at steady-state. Activity of the combination was observed. Accrual is ongoing to determine the MTD of ABT-888/C. This work is supported by NCI U01-CA132194 (NJ) and NCI U01-CA099168 (PA). No significant financial relationships to disclose.